Medicine
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CLINICAL TRIAL/EXPERIMENTAL STUDY
Internal Mammary Sentinel Lymph Node Biopsy With Modified Injection Technique High Visualization Rate and Accurate Staging Peng-Fei Qiu, MD, Bin-Bin Cong, MD, Rong-Rong Zhao, MS, Guo-Ren Yang, MD, Yan-Bing Liu, MD, Peng Chen, MD, and Yong-Sheng Wang, MD, PhD
Abstract: Although the 2009 American Joint Committee on Cancer incorporated the internal mammary sentinel lymph node biopsy (IMSLNB) concept, there has been little change in surgical practice patterns because of the low visualization rate of internal mammary sentinel lymph nodes (IMSLN) with the traditional radiotracer injection technique. In this study, various injection techniques were evaluated in term of the IMSLN visualization rate, and the impact of IM-SLNB on the diagnostic and prognostic value were analyzed. Clinically, axillary lymph nodes (ALN) negative patients (n ¼ 407) were divided into group A (traditional peritumoral intraparenchymal injection) and group B (modified periareolar intraparenchymal injection). Group B was then separated into group B1 (low volume) and group B2 (high volume) according to the injection volume. Clinically, ALN-positive patients (n ¼ 63) were managed as group B2. Internal mammary sentinel lymph node biopsy was performed for patients with IMSLN visualized. The IMSLN visualization rate was significantly higher in group B than that in group A (71.1% versus 15.5%, P < 0.001), whereas the axillary sentinel lymph nodes were reliably identified in both groups (98.9% versus 98.3%, P ¼ 0.712). With high injection volume, group B2 was found to have higher IMSLN visualization rate than group B1 (75.1% versus 45.8%, P < 0.001). The IMSLN metastasis rate was only 8.1% (12/ 149) in clinically ALN-negative patients with successful IM-SLNB, and adjuvant treatment was altered in a small proportion. The IMSLN visualization rate was 69.8% (44/63) in clinically ALN-positive patients with the IMSLN metastasis rate up to 20.5% (9/44), and individual radiotherapy strategy could be guided with the IM-SLNB results. The modified injection technique (periareolar intraparenchymal, high volume, and ultrasound guidance) significantly improved the IMSLN visualization rate, making the routine IM-SLNB possible in daily practice. Internal mammary sentinel lymph node biopsy could provide individual minimally invasive staging, prognosis, and decision making of the internal mammary radiotherapy, especially for clinically ALNpositive patients. (Medicine 94(41):e1790)
Editor: Perbinder Grewal. Received: July 21, 2015; revised: September 3, 2015; accepted: September 14, 2015. From the Breast Cancer Center (PFQ, BBC, RRZ, YBL, PC, YSW) and Department of Nuclear Medicine (GRY), Shandong Cancer Hospital and Institute, Jinan, Shandong, China. Correspondence: Yong-Sheng Wang, MD, PhD, Breast Cancer Center, Shandong Cancer Hospital and Institute, 440 Jiyan Rd, Jinan, Shandong, 250117, China (e-mail: [email protected]). The authors have no conflicts of interest to disclose. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000001790
Medicine
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Abbreviations: ACR = American College of Radiology, ALN = axillary lymph nodes, BMI = body mass index, IMLN = internal mammary lymph nodes, IMSLN = internal mammary sentinel lymph nodes, IM-SLNB = internal mammary sentinel lymph node biopsy, LIQ = lower inner quadrant, LOQ = lower outer quadrant, SLN = sentinel lymph nodes, SLNB = sentinel lymph node biopsy, UIQ = upper inner quadrant, UOQ = upper outer quadrant.
INTRODUCTION
A
s the first-echelon nodal drainage sites of breast cancer, the status of axillary lymph nodes (ALN) and internal mammary lymph nodes (IMLN) is valuable both for regional staging and treatment choice. The status of ALN could be routinely evaluated with sentinel lymph node biopsy (SLNB) and/or surgical dissection. Accurate regional staging, however, could not be achieved by depending on the status of the ALN alone, which might lead to understage and under/overtreatment. Interest in metastasis to IMLN culminated with the extended radical mastectomy,1 but this radical surgical procedure was abandoned because of its extra complications, longer operation time, and no survival benefit.2 With the widespread application of effective systemic therapy in the era of molecular subtyping today, it is worth rethinking about whether or not this conclusion in the 1950s still fits into todays’ clinical practice. Recently, a meta-analysis, including the MA.20 (n ¼ 1832), the EORTC 22922/10925 (n ¼ 4004), and the French trial (n ¼ 1334) shows that additional regional radiotherapy to the IMLN and medial supraclavicular lymph nodes significantly improves the disease-free survival, distant metastasis free survival, and overall survival in stage I to III breast cancer.3 The inclusion criteria (high-risk patients/no histopathologic confirmation of IMLN) in these studies, however, meant that they could not identify patients who would really benefit from adjuvant radiotherapy, and individual IMLN radiotherapy could not be performed. The internal mammary sentinel lymph node biopsy (IM-SLNB) is a less invasive method for evaluating IMLN than surgical dissection, and this might refine regional staging and allow individual IMLN radiotherapy. Although the 2009 American Joint Committee on Cancer staging incorporated the IM-SLNB concept, there, however, has been little change in surgical practice patterns of IM-SLNB because of the low visualization rate of internal mammary sentinel lymph nodes (IMSLN) with the traditional injection technique.4– 6 Several studies have discovered that superficial injection (intradermal, subdermal, periareolar, and subareolar) of radiotracer was hard to identify IMSLN, whereas intraparenchymal injection (peritumoral, intratumoral, or subtumoral) was more reliable.4,7– 10 These results suggest that the dermal and subdermal lymphatic flow is rarely directed to the internal www.md-journal.com |
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mammary region, whereas some intraparenchymal lymphatic flow is directed to the internal mammary region. Unfortunately, with the traditional intraparenchymal injection technique, the internal mammary hotspots were only seen in a small proportion of patients (average 13%, range 0%–37%), which has restricted the clinical studies and daily practice of IM-SLNB to date.4 –6,11 In the current study, various injection techniques were evaluated in term of the IMSLN visualization rate in clinically ALN-negative patients, and the impact of IM-SLNB on staging, prognosis, and prediction of systemic and regional radiotherapy were analyzed both in clinically ALN-negative (NCT01642511) and ALN-positive patients (NCT01668914).
METHODS From January 2012 to March 2015, 470 patients (clinically ALN-negative 407 and positive 63) from Shandong Cancer Hospital with biopsy-proven invasive breast cancer were enrolled in this study. The median age was 47 years (range, 24–80 years). The exclusion criteria included pregnancy, metastatic breast cancer, and neoadjuvant chemotherapy. The study was approved by the ethics committee and each patient provided informed consent.
Radiotracer Injection and Grouping
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fine needle aspiration cytology were also included) were classified into 2 groups according to exploratory stage and radiotracer injection technique:
Traditional Technique: Group A (Peritumoral Intraparenchymal Injection) The first 58 patients were enrolled in this group between January 2012 and April 2012, the median age of patients was 45.5 years (range, 26–70 years). Each patient received an intraparenchymal injection of 99mTc-SC (18.5–44.4 MBq/ 0.4–1.0 mL) at 1 to 2 points surrounding the primary tumor.
Modified Technique: Group B (Periareolar Intraparenchymal Injection) A total of 349 patients were included in this group from May 2012 to November 2014. The median age of patients was 48 years (range, 24–80 years). Two syringes of 9.25 to 18.5 MBq 99mTcSC in 0.2 to 0.7 mL volume were injected intraparenchymally at the 6 and 12 o’clock positions 0.5 to1.0 cm from areola (about 2.0–4.0 cm from the nipple) (Fig. 1). Group B was then separated into 2 groups according to the radiotracer injection volume: group B1, low volume ( 0.05; Table 3). The radiotracer injection volume were analyzed in group B, and the IMSLN visualization rate for patients with 0.2, 0.3 0.4, 0.5, 0.6, and 0.7 mL/point injection volume was 38.5%, 42.9%, 52.4%, 71.9%, 78.7%, and 85.7%, respectively (Figure 3). The internal mammary hotspots were more frequently seen in patients with high volume of radiotracer (group B2: 0.5 mL/point) compared those with low volume (group B1: 0.05, data not shown), and the IMSLN visualization rate was similar in both groups (69.8% versus 75.1%, P ¼ 0.388).
Sample Size Results of previous studies showed that approximately 13% (from 0% to 37%) of IMSLN were identified after traditional peritumoral injection.4–11 To be able to detect an improvement of IMSLN visualization rate at least 50% in the modified injection group, at the 5% significance level, minimum 31 patients per group were required to reach a power of 90% (2-sided test).12
Statistical Analysis The data were analyzed with the SPSS 17.0 software package. x2 test or Fisher exact test was performed to compare the visualization rates among the groups, and the t test or Mann– Whitney test was used to compare the differences in means between the groups. A P value 50 BMI Median Range Mammographic density ACR 1 ACR 2 ACR 3 ACR 4 Tumor size T1 T2 T3 Tumor location UOQ LOQ UIQ LIQ Central Tumor type Ductal Lobular Mixed Other Radiotracer intensity, MBq Radiotracer volume, mL/point Time intervals between injection and SLNB 3–5 hours 16–18 hours
58
349
45.5 26–70 43 15
48 24–80 74.1 25.9
23.2 17.9–31.2
24.0 16.7–36.5
1 33 22 2
1.7 56.9 37.9 3.4
19 173 148 9
5.4 49.6 42.4 2.6
31 26 1
53.4 44.8 1.7
191 151 7
54.7 43.3 2.0
25 12 14 5 2
43.1 20.7 24.1 8.6 3.4
181 35 80 18 35
51.9 10.0 22.9 5.2 10.0
49 3 2 4 36.667
84.5 5.2 3.4 6.9 33.855
310 12 8 19 0.099
88.8 3.4 2.3 5.4
0.478
0.515
0.222
P 0.102
220 129
63.0 37.0 0.227
0.904
0.876
0.700
0.352
0.823 27 31
46.6 53.4
168 181
48.1 51.9
ACR ¼ American College of Radiology, BMI ¼ body mass index, LIQ ¼ lower inner quadrant, LOQ ¼ lower outer quadrant, UIQ ¼ upper inner quadrant, UOQ ¼ upper outer quadrant. Mammographic density was assessed by 2 radiologists of the University Hospital Ulm applying the classification of the ACR including 4 categories: ACR 1 ¼ almost entirely fat, glandular tissue < 25%, ACR 2 ¼ scattered fibroglandular densities (ca. 25–50% of breast), ACR 3 ¼ heterogeneously breast dense (ca. 51–75% of breast), and ACR 4 ¼ extremely dense (>75% of breast).
DISCUSSION In addition to the ALN, the IMLN drainage is also an important lymphatic channel of the breast. The National Comprehensive Cancer Network Clinical Practice Guidelines recommend to strongly consider radiotherapy to IMLN for patients with positive ALN or tumor >5 cm (category 2B), noting ‘‘radiotherapy should be given to the IMLN that are clinically or pathologically positive; otherwise the treatment to the IMLN is at the discretion of the treating radiation oncologist’’ on this topic.13 A minimally invasive method, however, is still lacked to evaluate the status of IMLN, and individual IMLN radiotherapy could not be performed.
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The IM-SLNB is a less invasive method for assessing IMLN than surgical dissection, and may affect decision making for regional and systemic therapy.4 Unfortunately, the internal mammary hotspots are only visualized in a small proportion of patients (average 13%, range 0%–37%) with the traditional injection technique, which has restricted the clinical studies and daily practice of IM-SLNB to date.4– 6,11 In the initial stage of this study, the IMSLN visualization rate was 15.5% in patients with traditional peritumoral injection, and this result was in accordance with the previous studies (Table 4).7– 10,14,15 Current evidence has shown that the ASLN receive the lymphatic drainage from not only the primary tumor area, but Copyright
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Internal Mammary Sentinel Lymph Node Biopsy
TABLE 2. Sentinel Lymph Nodes Visualization by Preoperative Lymphoscintigraphy Group A (Traditional Technique) Characteristic
No.
%
No. of patients Location of SLN Total axilla Total internal mammary Axilla only Internal mammary only Axilla þ internal mammary No location
58 46 45 8 38 1 7 12
349 79.3 77.6 13.8 65.5 1.7 12.1 20.7
Group B (Modified Technique) No. 325 297 222 103 28 194 24
% 93.1 87.4 63.6 29.5 8.0 55.6 6.9
SLN ¼ sentinel lymph nodes.
also the entire breast organ.16,17 Tanis et al18 described that the breast parenchyma has extensive lymphatic network and has rich anastomoses with the superficial cutaneous lymph plexus of the developing skin. It is considered that radiotracer, wherever injected, could flow to the same ASLN. Based on the above new concept of ASLN, we hypothesized that the IMSLN receive lymphatic drainage from not only the primary tumor area, but also the entire breast organ (in other words, the radiotracer could flow to the same IMSLN wherever injected). Based on this hypothesis of the internal mammary lymphatic drainage pattern, we injected radiotracer intraparenchymally into 2 sites of the breast to achieve a relatively high visualization rate of IMSLN. The injection sites were chosen at the 6 and 12 o’clock positions 0.5 to 1.0 cm from areola (about 2.0–4.0 cm from the nipple), because the parenchyma was relatively rich as compared with the tumor site, and the shine-through phenomenon could be avoided as compared with 3 and 9 o’clock positions.19 Meanwhile, the IMSLN detected by our modified technique (6 and
TABLE 3. Characteristic Correlation in Patients With Internal Mammary Sentinel Lymph Nodes Visualization IMSLN Identification Characteristic
Yes
No
No. of patients Age, years Median Range BMI Median Range Mammographic density ACR 1 ACR 2 ACR 3 ACR 4 Tumor size T1 T2 T3 Tumor location UOQ LOQ UIQ LIQ Central Tumor type Ductal Lobular Mixed Other Radiotracer intensity, MBq Radiotracer volume, mL/point Time intervals between injection and SLNB 3–5 hours 16–18 hours
248
101
47 24–79
49 31–80
23.9 16.7–36.5
24.1 17.2–32.0
P 0.057
0.488
0.553 10 126 105 7
9 47 43 2
132 111 5
59 40 2
131 26 54 12 25
50 9 26 6 10
221 8 5 14 33.633
89 4 3 5 34.373
0.124
0.530
0.479
0.002
0.079
0.535
0.814
0.082
112 136
56 45
ACR ¼ American College of Radiology, BMI ¼ body mass index, IMSLN ¼ internal mammary sentinel lymph nodes, LIQ ¼ lower inner quadrant, LOQ ¼ lower outer quadrant, SLNB ¼ sentinel lymph node biopsy, UIQ ¼ upper inner quadrant, UOQ ¼ upper outer quadrant.
FIGURE 2. Sentinel lymph nodes visualization rate according to different group by preoperative lymphoscintigraphy and/or intraoperative gamma probe.
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12 o’clock positions periareolar intraparenchymal injection) were concentrated in the second and third intercostal space, which were consistent with the traditional technique (peritumoral intraparenchymal injection),4 –6 and also coincided with the sites of IMLN metastasis, which was reported in the previous studies of extended radical mastectomy.20,21 These results indirectly confirmed our hypothesis of the internal mammary lymphatic drainage pattern. The visualization rate of IMSLN is partially associated with breast density,6,22 and local pressure at the injection site could be increased with a high volume of radiotracer, which contributed to IMSLN visualization. In current study, the www.md-journal.com |
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FIGURE 3. Internal mammary sentinel lymph nodes visualization rates according to different injection volume.
FIGURE 4. The distribution location of internal mammary sentinel lymph nodes.
internal mammary hotspots were commonly seen in patients who were injected with a higher volume of radiotracer. For this reason, we divided group B into 2 groups, according to the radiotracer injection volume, and found that the IMSLN visualization rate could be further improved with high injection volume. Another technical issue, which could affect the IMSLN visualization rate is how to ensure the radiotracer is injected intraparenchymally. Intraparenchymal injection requires considerable experience, and it is often difficult to inject radiotracer into the parenchyma to the correct depth. Thus, the variation in IMSLN visualization rate between different studies could be partially attributed to the technical differences in radiotracer injection.7– 10 In our study, the radiotracer was injected under ultrasound guidance, and the accuracy of injection depth was
guaranteed so that the radiotracer was drained to the internal mammary region. Owing to such a high IMSLN visualization rate with our modified injection technique, more clinical benefit would be emerged. As IM-SLNB leads to more complete regional staging,23 it provides guidance for tailored regional therapy, with maximal benefit and minimal invasion. Recently, several studies reported that radiotherapy to the IMLN and medial supraclavicular lymph nodes could improve breast cancer survival in high-risk IMLN metastasis patients (positive ALN and/or medial/central tumor location).24,25 These eligibility criteria, however, might induce over- and undertreatment, because high risk did not mean IMLN metastasis and low risk did not mean IMLN negative. Because IMLN radiotherapy increased cardiac and pulmonary side effects, the appropriate identification of
TABLE 4. Studies of Sentinel Lymph Nodes Visualization With Different Injection Site (No. (%)) Successful Visualization Authors
Year
No. of Patients
Injection Site
Axilla
Shimazu7
2003
Park8
2005
Rodier9
2007
Garcia-Manero10
2010
Wang14 (our center) Sun15 (our center) This study
2007 2010 2015
41 40 70 45 83 58 216 216 74 59 636 290 58 349
Intraparenchymal (peritumoral) Intraparenchymal (subtumoral) Periareolar Intradermal Intraparenchymal (peritumoral) Intradermal Intraparenchymal (peritumoral) Periareolar Intraparenchymal (intratumoral) Periareolar Subdermal Subdermal Intraparenchymal (peritumoral) Intraparenchymal (periareolar)
20 28 59 39
(48.8) (70.0) (84.3) (86.7) NA NA 158 (73.2) 184 (85.2) 72 (97.3) 59 (100) 625 (98.3) 286 (98.6) 57 (98.3) 345 (98.9)
Internal Mammary 1 (2.4) 15 (37.5) 3 (4.3) 0 14 (16.9) 0 29 (13.4) 13 (6.0) 8 (10.8) 0 25 (3.9) 4 (1.4) 9 (15.5) 248 (71.1)
SLN ¼ sentinel lymph nodes.
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patients who could benefit from adjuvant radiotherapy is essential, and should be based on IM-SLN metastasis rather than high-risk estimation only. Internal mammary lymph nodes radiotherapy should be tailored and balanced between the potential benefit and toxicity, and IM-SLNB guidance could achieve this goal.26 Although several studies indicated that the presence of IMSLN metastasis rarely influenced adjuvant treatment strategy and did not affect overall survival,5,6,27 it should be interpreted with caution for the limitation of their study population. Studies of SLNB (both axilla and internal mammary) have been limited to the clinically ALN-negative patients, and it is adequate for the axillary staging. More attention, however, should be focused on the IM-SLNB in clinically ALN-positive patients, as IMLN metastasis is mostly found concomitantly with ALN metastasis.21 In our study, the IMSLN metastasis rate was only 8.1% in clinically ALN-negative patient, and adjuvant treatment was altered in a small proportion. The IMSLN metastasis rate was 20.5% in clinically ALN-positive patients, and individual radiotherapy strategy, however, could be guided with the IM-SLNB results. As a consequence, previous IMSLNB studies failed to evaluate the status of IMLN who really were in need; we can see from the above results that there are a group of patients (clinically ALN-positive) who could really benefit from the IM-SLNB. The basic problem in this study is the same as all the previous research: unlike in the axilla, a backup lymph node dissection have been performed, we could not verify the accuracy of IM-SLNB directly. Although the distribution of IMSLN detected by our modified technique exactly coincides with the sites of IMLN metastasis, which was reported in the previous studies of extended radical mastectomy,20,21 validation study (eg, involving IM-SLNB followed by complete IMLN dissection) should be required to confirm that the IMSLN could accurately reflect the nodal status of internal mammary basin before the clinical application of IM-SLNB. In conclusion, the modified injection technique (periareolar intraparenchymal, high volume, and ultrasound guidance) significantly improved the IMSLN visualization rate, making the routine IM-SLNB possible in daily practice. Internal mammary sentinel lymph node biopsy could provide individual minimally invasive staging, prognosis, and decision making of the internal mammary radiotherapy for breast cancer patients, especially for clinically ALN-positive patients. REFERENCES
Internal Mammary Sentinel Lymph Node Biopsy
6. Heuts EM, van der Ent FW, von Meyenfeldt MF, et al. Internal mammary lymph drainage and sentinel node biopsy in breast cancer – a study on 1008 patients. Eur J Surg Oncol. 2009;35:252–257. 7. Shimazu K, Tamaki Y, Taguchi T, et al. Lymphoscintigraphic visualization of internal mammary nodes with subtumoral injection of radiocolloid in patients with breast cancer. Ann Surg. 2003;237:390–398. 8. Park C, Seid P, Morita E, et al. Internal mammary sentinel lymph node mapping for invasive breast cancer: implications for staging and treatment. Breast J. 2005;11:29–33. 9. Rodier JF, Velten M, Wilt M, et al. Prospective multicentric randomized study comparing periareolar and peritumoral injection of radiotracer and blue dye for the detection of sentinel lymph node in breast sparing procedures: FRANSENODE trial. J Clin Oncol. 2007;25:3664–3669. 10. Garcia-Manero M, Olartecoechea B, Royo P. Different injection sites of radionuclide for sentinel lymph node detection in breast cancer: single institution experience. Eur J Obstet Gynecol Reprod Biol. 2010;153:185–187. 11. Caudle AS, Yi M, Hoffman KE, et al. Impact of identification of internal mammary sentinel lymph node metastasis in breast cancer patients. Ann Surg Oncol. 2014;21:60–65. 12. Jones SR1, Carley S, Harrison M. An introduction to power and sample size estimation. Emerg Med J. 2003;20:453–458. 13. National Comprehensive Cancer Network. NCCN Breast Cancer Clinical Practice Guidelines in Oncology. (V. 1.2015). http:// www.nccn.org/professionals/physician_gls/PDF/breast.pdf 14. Wang L, Yu JM, Wang YS, et al. Preoperative lymphoscintigraphy predicts the successful identification but is not necessary in sentinel lymph nodes biopsy in breast cancer. Ann Surg Oncol. 2007;14:2215–2220. 15. Sun X, Liu JJ, Wang YS, et al. Roles of preoperative lymphoscintigraphy for sentinel lymph node biopsy in breast cancer patients. Jpn J Clin Oncol. 2010;40:722–725. 16. Chagpar A, Martin RC 3rd, Chao C, et al. Validation of subareolar and periareolar injection techniques for breast sentinel lymph node biopsy. Arch Surg. 2004;139:614–618. 17. Borgstein PJ, Meijer S, Pijpers RJ, et al. Functional lymphatic anatomy for sentinel node biopsy in breast cancer: echoes from the past and the periareolar blue method. Ann Surg. 2000;232:81–89. 18. Tanis PJ, Nieweg OE, Valde´s Olmos RA, et al. Anatomy and physiology of lymphatic drainage of the breast from the perspective of sentinel node biopsy. J Am Coll Surg. 2001;192:399–409. 19. Qiu PF, Liu JJ, Liu YB, et al. A modified technology could significantly improve the visualization rate of the internal mammary sentinel lymph nodes in breast cancer patients. Breast Cancer Res Treat. 2012;136:319–321.
1. Veronesi U, Cascinelli N, Greco M, et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg. 1985;202:702–707.
20. Livingston SF, Arlen M. The extended extrapleural radical mastectomy: its role in the treatment of carcinoma of the breast. Ann Surg. 1974;179:260–265.
2. Veronesi U, Marubini E, Mariani L, et al. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer. 1999;35:1320–1325.
21. Huang O, Wang L, Shen K, et al. Breast cancer subpopulation with high risk of internal mammary lymph nodes metastasis: analysis of 2,269 Chinese breast cancer patients treated with extended radical mastectomy. Breast Cancer Res Treat. 2008;107:379–387.
3. Budach W, Kammers K, Boelke E, et al. Adjuvant radiotherapy of regional lymph nodes in breast cancer: a meta-analysis of randomized trials. Radiat Oncol. 2013;8:267.
22. Madsen EVE, Gobardhan PD, Bongers V, et al. The impact on postsurgical treatment of sentinel lymph node biopsy of internal mammary lymph nodes in patients with breast cancer. Ann Surg Oncol. 2007;14:1486–1492.
4. Chen RC, Lin NU, Golshan M, et al. Internal mammary nodes in breast cancer: diagnosis and implications for patient management—a systematic review. J Clin Oncol. 2008;26:4981–4989. 5. Postma EL, van Wieringen S, Hobbelink MG, et al. Sentinel lymph node biopsy of the internal mammary chain in breast cancer. Breast Cancer Res Treat. 2012;134:735–741.
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23. Gnerlich JL, Barreto-Andrade JC, Czechura T, et al. Accurate staging with internal mammary chain sentinel node biopsy for breast cancer. Ann Surg Oncol. 2014;21:368–374. 24. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group). Effect of radiotherapy after mastectomy and axillary surgery on
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10-year recurrence and 20-year breast cancer mortality: metaanalysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127–2135. 25. Poortmans P, Struikmans H, Kirkove C. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 years results of the EORTC Radiation Oncology and Breast Cancer Groups phase III trial 22292/10925 (meeting abstracts). Eur J Cancer. 2013;49:BA2.
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26. Cong BB, Qiu PF, Wang YS. Internal mammary sentinel lymph node biopsy: minimally invasive staging and tailored internal mammary radiotherapy. Ann Surg Oncol. 2014;21:2119– 2121. 27. Madsen EV, Aalders KC, van der Heiden-van der Loo M, et al. Prognostic significance of tumor-positive internal mammary sentinel lymph nodes in breast cancer: a multicenter cohort study. Ann Surg Oncol. 2015. [Epub ahead of print].
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®
CLINICAL TRIAL/EXPERIMENTAL STUDY
Internal Mammary Sentinel Lymph Node Biopsy With Modified Injection Technique High Visualization Rate and Accurate Staging Peng-Fei Qiu, MD, Bin-Bin Cong, MD, Rong-Rong Zhao, MS, Guo-Ren Yang, MD, Yan-Bing Liu, MD, Peng Chen, MD, and Yong-Sheng Wang, MD, PhD
Abstract: Although the 2009 American Joint Committee on Cancer incorporated the internal mammary sentinel lymph node biopsy (IMSLNB) concept, there has been little change in surgical practice patterns because of the low visualization rate of internal mammary sentinel lymph nodes (IMSLN) with the traditional radiotracer injection technique. In this study, various injection techniques were evaluated in term of the IMSLN visualization rate, and the impact of IM-SLNB on the diagnostic and prognostic value were analyzed. Clinically, axillary lymph nodes (ALN) negative patients (n ¼ 407) were divided into group A (traditional peritumoral intraparenchymal injection) and group B (modified periareolar intraparenchymal injection). Group B was then separated into group B1 (low volume) and group B2 (high volume) according to the injection volume. Clinically, ALN-positive patients (n ¼ 63) were managed as group B2. Internal mammary sentinel lymph node biopsy was performed for patients with IMSLN visualized. The IMSLN visualization rate was significantly higher in group B than that in group A (71.1% versus 15.5%, P < 0.001), whereas the axillary sentinel lymph nodes were reliably identified in both groups (98.9% versus 98.3%, P ¼ 0.712). With high injection volume, group B2 was found to have higher IMSLN visualization rate than group B1 (75.1% versus 45.8%, P < 0.001). The IMSLN metastasis rate was only 8.1% (12/ 149) in clinically ALN-negative patients with successful IM-SLNB, and adjuvant treatment was altered in a small proportion. The IMSLN visualization rate was 69.8% (44/63) in clinically ALN-positive patients with the IMSLN metastasis rate up to 20.5% (9/44), and individual radiotherapy strategy could be guided with the IM-SLNB results. The modified injection technique (periareolar intraparenchymal, high volume, and ultrasound guidance) significantly improved the IMSLN visualization rate, making the routine IM-SLNB possible in daily practice. Internal mammary sentinel lymph node biopsy could provide individual minimally invasive staging, prognosis, and decision making of the internal mammary radiotherapy, especially for clinically ALNpositive patients. (Medicine 94(41):e1790)
Editor: Perbinder Grewal. Received: July 21, 2015; revised: September 3, 2015; accepted: September 14, 2015. From the Breast Cancer Center (PFQ, BBC, RRZ, YBL, PC, YSW) and Department of Nuclear Medicine (GRY), Shandong Cancer Hospital and Institute, Jinan, Shandong, China. Correspondence: Yong-Sheng Wang, MD, PhD, Breast Cancer Center, Shandong Cancer Hospital and Institute, 440 Jiyan Rd, Jinan, Shandong, 250117, China (e-mail: [email protected]). The authors have no conflicts of interest to disclose. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000001790
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Abbreviations: ACR = American College of Radiology, ALN = axillary lymph nodes, BMI = body mass index, IMLN = internal mammary lymph nodes, IMSLN = internal mammary sentinel lymph nodes, IM-SLNB = internal mammary sentinel lymph node biopsy, LIQ = lower inner quadrant, LOQ = lower outer quadrant, SLN = sentinel lymph nodes, SLNB = sentinel lymph node biopsy, UIQ = upper inner quadrant, UOQ = upper outer quadrant.
INTRODUCTION
A
s the first-echelon nodal drainage sites of breast cancer, the status of axillary lymph nodes (ALN) and internal mammary lymph nodes (IMLN) is valuable both for regional staging and treatment choice. The status of ALN could be routinely evaluated with sentinel lymph node biopsy (SLNB) and/or surgical dissection. Accurate regional staging, however, could not be achieved by depending on the status of the ALN alone, which might lead to understage and under/overtreatment. Interest in metastasis to IMLN culminated with the extended radical mastectomy,1 but this radical surgical procedure was abandoned because of its extra complications, longer operation time, and no survival benefit.2 With the widespread application of effective systemic therapy in the era of molecular subtyping today, it is worth rethinking about whether or not this conclusion in the 1950s still fits into todays’ clinical practice. Recently, a meta-analysis, including the MA.20 (n ¼ 1832), the EORTC 22922/10925 (n ¼ 4004), and the French trial (n ¼ 1334) shows that additional regional radiotherapy to the IMLN and medial supraclavicular lymph nodes significantly improves the disease-free survival, distant metastasis free survival, and overall survival in stage I to III breast cancer.3 The inclusion criteria (high-risk patients/no histopathologic confirmation of IMLN) in these studies, however, meant that they could not identify patients who would really benefit from adjuvant radiotherapy, and individual IMLN radiotherapy could not be performed. The internal mammary sentinel lymph node biopsy (IM-SLNB) is a less invasive method for evaluating IMLN than surgical dissection, and this might refine regional staging and allow individual IMLN radiotherapy. Although the 2009 American Joint Committee on Cancer staging incorporated the IM-SLNB concept, there, however, has been little change in surgical practice patterns of IM-SLNB because of the low visualization rate of internal mammary sentinel lymph nodes (IMSLN) with the traditional injection technique.4– 6 Several studies have discovered that superficial injection (intradermal, subdermal, periareolar, and subareolar) of radiotracer was hard to identify IMSLN, whereas intraparenchymal injection (peritumoral, intratumoral, or subtumoral) was more reliable.4,7– 10 These results suggest that the dermal and subdermal lymphatic flow is rarely directed to the internal www.md-journal.com |
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mammary region, whereas some intraparenchymal lymphatic flow is directed to the internal mammary region. Unfortunately, with the traditional intraparenchymal injection technique, the internal mammary hotspots were only seen in a small proportion of patients (average 13%, range 0%–37%), which has restricted the clinical studies and daily practice of IM-SLNB to date.4 –6,11 In the current study, various injection techniques were evaluated in term of the IMSLN visualization rate in clinically ALN-negative patients, and the impact of IM-SLNB on staging, prognosis, and prediction of systemic and regional radiotherapy were analyzed both in clinically ALN-negative (NCT01642511) and ALN-positive patients (NCT01668914).
METHODS From January 2012 to March 2015, 470 patients (clinically ALN-negative 407 and positive 63) from Shandong Cancer Hospital with biopsy-proven invasive breast cancer were enrolled in this study. The median age was 47 years (range, 24–80 years). The exclusion criteria included pregnancy, metastatic breast cancer, and neoadjuvant chemotherapy. The study was approved by the ethics committee and each patient provided informed consent.
Radiotracer Injection and Grouping
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fine needle aspiration cytology were also included) were classified into 2 groups according to exploratory stage and radiotracer injection technique:
Traditional Technique: Group A (Peritumoral Intraparenchymal Injection) The first 58 patients were enrolled in this group between January 2012 and April 2012, the median age of patients was 45.5 years (range, 26–70 years). Each patient received an intraparenchymal injection of 99mTc-SC (18.5–44.4 MBq/ 0.4–1.0 mL) at 1 to 2 points surrounding the primary tumor.
Modified Technique: Group B (Periareolar Intraparenchymal Injection) A total of 349 patients were included in this group from May 2012 to November 2014. The median age of patients was 48 years (range, 24–80 years). Two syringes of 9.25 to 18.5 MBq 99mTcSC in 0.2 to 0.7 mL volume were injected intraparenchymally at the 6 and 12 o’clock positions 0.5 to1.0 cm from areola (about 2.0–4.0 cm from the nipple) (Fig. 1). Group B was then separated into 2 groups according to the radiotracer injection volume: group B1, low volume ( 0.05; Table 3). The radiotracer injection volume were analyzed in group B, and the IMSLN visualization rate for patients with 0.2, 0.3 0.4, 0.5, 0.6, and 0.7 mL/point injection volume was 38.5%, 42.9%, 52.4%, 71.9%, 78.7%, and 85.7%, respectively (Figure 3). The internal mammary hotspots were more frequently seen in patients with high volume of radiotracer (group B2: 0.5 mL/point) compared those with low volume (group B1: 0.05, data not shown), and the IMSLN visualization rate was similar in both groups (69.8% versus 75.1%, P ¼ 0.388).
Sample Size Results of previous studies showed that approximately 13% (from 0% to 37%) of IMSLN were identified after traditional peritumoral injection.4–11 To be able to detect an improvement of IMSLN visualization rate at least 50% in the modified injection group, at the 5% significance level, minimum 31 patients per group were required to reach a power of 90% (2-sided test).12
Statistical Analysis The data were analyzed with the SPSS 17.0 software package. x2 test or Fisher exact test was performed to compare the visualization rates among the groups, and the t test or Mann– Whitney test was used to compare the differences in means between the groups. A P value 50 BMI Median Range Mammographic density ACR 1 ACR 2 ACR 3 ACR 4 Tumor size T1 T2 T3 Tumor location UOQ LOQ UIQ LIQ Central Tumor type Ductal Lobular Mixed Other Radiotracer intensity, MBq Radiotracer volume, mL/point Time intervals between injection and SLNB 3–5 hours 16–18 hours
58
349
45.5 26–70 43 15
48 24–80 74.1 25.9
23.2 17.9–31.2
24.0 16.7–36.5
1 33 22 2
1.7 56.9 37.9 3.4
19 173 148 9
5.4 49.6 42.4 2.6
31 26 1
53.4 44.8 1.7
191 151 7
54.7 43.3 2.0
25 12 14 5 2
43.1 20.7 24.1 8.6 3.4
181 35 80 18 35
51.9 10.0 22.9 5.2 10.0
49 3 2 4 36.667
84.5 5.2 3.4 6.9 33.855
310 12 8 19 0.099
88.8 3.4 2.3 5.4
0.478
0.515
0.222
P 0.102
220 129
63.0 37.0 0.227
0.904
0.876
0.700
0.352
0.823 27 31
46.6 53.4
168 181
48.1 51.9
ACR ¼ American College of Radiology, BMI ¼ body mass index, LIQ ¼ lower inner quadrant, LOQ ¼ lower outer quadrant, UIQ ¼ upper inner quadrant, UOQ ¼ upper outer quadrant. Mammographic density was assessed by 2 radiologists of the University Hospital Ulm applying the classification of the ACR including 4 categories: ACR 1 ¼ almost entirely fat, glandular tissue < 25%, ACR 2 ¼ scattered fibroglandular densities (ca. 25–50% of breast), ACR 3 ¼ heterogeneously breast dense (ca. 51–75% of breast), and ACR 4 ¼ extremely dense (>75% of breast).
DISCUSSION In addition to the ALN, the IMLN drainage is also an important lymphatic channel of the breast. The National Comprehensive Cancer Network Clinical Practice Guidelines recommend to strongly consider radiotherapy to IMLN for patients with positive ALN or tumor >5 cm (category 2B), noting ‘‘radiotherapy should be given to the IMLN that are clinically or pathologically positive; otherwise the treatment to the IMLN is at the discretion of the treating radiation oncologist’’ on this topic.13 A minimally invasive method, however, is still lacked to evaluate the status of IMLN, and individual IMLN radiotherapy could not be performed.
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The IM-SLNB is a less invasive method for assessing IMLN than surgical dissection, and may affect decision making for regional and systemic therapy.4 Unfortunately, the internal mammary hotspots are only visualized in a small proportion of patients (average 13%, range 0%–37%) with the traditional injection technique, which has restricted the clinical studies and daily practice of IM-SLNB to date.4– 6,11 In the initial stage of this study, the IMSLN visualization rate was 15.5% in patients with traditional peritumoral injection, and this result was in accordance with the previous studies (Table 4).7– 10,14,15 Current evidence has shown that the ASLN receive the lymphatic drainage from not only the primary tumor area, but Copyright
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Internal Mammary Sentinel Lymph Node Biopsy
TABLE 2. Sentinel Lymph Nodes Visualization by Preoperative Lymphoscintigraphy Group A (Traditional Technique) Characteristic
No.
%
No. of patients Location of SLN Total axilla Total internal mammary Axilla only Internal mammary only Axilla þ internal mammary No location
58 46 45 8 38 1 7 12
349 79.3 77.6 13.8 65.5 1.7 12.1 20.7
Group B (Modified Technique) No. 325 297 222 103 28 194 24
% 93.1 87.4 63.6 29.5 8.0 55.6 6.9
SLN ¼ sentinel lymph nodes.
also the entire breast organ.16,17 Tanis et al18 described that the breast parenchyma has extensive lymphatic network and has rich anastomoses with the superficial cutaneous lymph plexus of the developing skin. It is considered that radiotracer, wherever injected, could flow to the same ASLN. Based on the above new concept of ASLN, we hypothesized that the IMSLN receive lymphatic drainage from not only the primary tumor area, but also the entire breast organ (in other words, the radiotracer could flow to the same IMSLN wherever injected). Based on this hypothesis of the internal mammary lymphatic drainage pattern, we injected radiotracer intraparenchymally into 2 sites of the breast to achieve a relatively high visualization rate of IMSLN. The injection sites were chosen at the 6 and 12 o’clock positions 0.5 to 1.0 cm from areola (about 2.0–4.0 cm from the nipple), because the parenchyma was relatively rich as compared with the tumor site, and the shine-through phenomenon could be avoided as compared with 3 and 9 o’clock positions.19 Meanwhile, the IMSLN detected by our modified technique (6 and
TABLE 3. Characteristic Correlation in Patients With Internal Mammary Sentinel Lymph Nodes Visualization IMSLN Identification Characteristic
Yes
No
No. of patients Age, years Median Range BMI Median Range Mammographic density ACR 1 ACR 2 ACR 3 ACR 4 Tumor size T1 T2 T3 Tumor location UOQ LOQ UIQ LIQ Central Tumor type Ductal Lobular Mixed Other Radiotracer intensity, MBq Radiotracer volume, mL/point Time intervals between injection and SLNB 3–5 hours 16–18 hours
248
101
47 24–79
49 31–80
23.9 16.7–36.5
24.1 17.2–32.0
P 0.057
0.488
0.553 10 126 105 7
9 47 43 2
132 111 5
59 40 2
131 26 54 12 25
50 9 26 6 10
221 8 5 14 33.633
89 4 3 5 34.373
0.124
0.530
0.479
0.002
0.079
0.535
0.814
0.082
112 136
56 45
ACR ¼ American College of Radiology, BMI ¼ body mass index, IMSLN ¼ internal mammary sentinel lymph nodes, LIQ ¼ lower inner quadrant, LOQ ¼ lower outer quadrant, SLNB ¼ sentinel lymph node biopsy, UIQ ¼ upper inner quadrant, UOQ ¼ upper outer quadrant.
FIGURE 2. Sentinel lymph nodes visualization rate according to different group by preoperative lymphoscintigraphy and/or intraoperative gamma probe.
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12 o’clock positions periareolar intraparenchymal injection) were concentrated in the second and third intercostal space, which were consistent with the traditional technique (peritumoral intraparenchymal injection),4 –6 and also coincided with the sites of IMLN metastasis, which was reported in the previous studies of extended radical mastectomy.20,21 These results indirectly confirmed our hypothesis of the internal mammary lymphatic drainage pattern. The visualization rate of IMSLN is partially associated with breast density,6,22 and local pressure at the injection site could be increased with a high volume of radiotracer, which contributed to IMSLN visualization. In current study, the www.md-journal.com |
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FIGURE 3. Internal mammary sentinel lymph nodes visualization rates according to different injection volume.
FIGURE 4. The distribution location of internal mammary sentinel lymph nodes.
internal mammary hotspots were commonly seen in patients who were injected with a higher volume of radiotracer. For this reason, we divided group B into 2 groups, according to the radiotracer injection volume, and found that the IMSLN visualization rate could be further improved with high injection volume. Another technical issue, which could affect the IMSLN visualization rate is how to ensure the radiotracer is injected intraparenchymally. Intraparenchymal injection requires considerable experience, and it is often difficult to inject radiotracer into the parenchyma to the correct depth. Thus, the variation in IMSLN visualization rate between different studies could be partially attributed to the technical differences in radiotracer injection.7– 10 In our study, the radiotracer was injected under ultrasound guidance, and the accuracy of injection depth was
guaranteed so that the radiotracer was drained to the internal mammary region. Owing to such a high IMSLN visualization rate with our modified injection technique, more clinical benefit would be emerged. As IM-SLNB leads to more complete regional staging,23 it provides guidance for tailored regional therapy, with maximal benefit and minimal invasion. Recently, several studies reported that radiotherapy to the IMLN and medial supraclavicular lymph nodes could improve breast cancer survival in high-risk IMLN metastasis patients (positive ALN and/or medial/central tumor location).24,25 These eligibility criteria, however, might induce over- and undertreatment, because high risk did not mean IMLN metastasis and low risk did not mean IMLN negative. Because IMLN radiotherapy increased cardiac and pulmonary side effects, the appropriate identification of
TABLE 4. Studies of Sentinel Lymph Nodes Visualization With Different Injection Site (No. (%)) Successful Visualization Authors
Year
No. of Patients
Injection Site
Axilla
Shimazu7
2003
Park8
2005
Rodier9
2007
Garcia-Manero10
2010
Wang14 (our center) Sun15 (our center) This study
2007 2010 2015
41 40 70 45 83 58 216 216 74 59 636 290 58 349
Intraparenchymal (peritumoral) Intraparenchymal (subtumoral) Periareolar Intradermal Intraparenchymal (peritumoral) Intradermal Intraparenchymal (peritumoral) Periareolar Intraparenchymal (intratumoral) Periareolar Subdermal Subdermal Intraparenchymal (peritumoral) Intraparenchymal (periareolar)
20 28 59 39
(48.8) (70.0) (84.3) (86.7) NA NA 158 (73.2) 184 (85.2) 72 (97.3) 59 (100) 625 (98.3) 286 (98.6) 57 (98.3) 345 (98.9)
Internal Mammary 1 (2.4) 15 (37.5) 3 (4.3) 0 14 (16.9) 0 29 (13.4) 13 (6.0) 8 (10.8) 0 25 (3.9) 4 (1.4) 9 (15.5) 248 (71.1)
SLN ¼ sentinel lymph nodes.
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patients who could benefit from adjuvant radiotherapy is essential, and should be based on IM-SLN metastasis rather than high-risk estimation only. Internal mammary lymph nodes radiotherapy should be tailored and balanced between the potential benefit and toxicity, and IM-SLNB guidance could achieve this goal.26 Although several studies indicated that the presence of IMSLN metastasis rarely influenced adjuvant treatment strategy and did not affect overall survival,5,6,27 it should be interpreted with caution for the limitation of their study population. Studies of SLNB (both axilla and internal mammary) have been limited to the clinically ALN-negative patients, and it is adequate for the axillary staging. More attention, however, should be focused on the IM-SLNB in clinically ALN-positive patients, as IMLN metastasis is mostly found concomitantly with ALN metastasis.21 In our study, the IMSLN metastasis rate was only 8.1% in clinically ALN-negative patient, and adjuvant treatment was altered in a small proportion. The IMSLN metastasis rate was 20.5% in clinically ALN-positive patients, and individual radiotherapy strategy, however, could be guided with the IM-SLNB results. As a consequence, previous IMSLNB studies failed to evaluate the status of IMLN who really were in need; we can see from the above results that there are a group of patients (clinically ALN-positive) who could really benefit from the IM-SLNB. The basic problem in this study is the same as all the previous research: unlike in the axilla, a backup lymph node dissection have been performed, we could not verify the accuracy of IM-SLNB directly. Although the distribution of IMSLN detected by our modified technique exactly coincides with the sites of IMLN metastasis, which was reported in the previous studies of extended radical mastectomy,20,21 validation study (eg, involving IM-SLNB followed by complete IMLN dissection) should be required to confirm that the IMSLN could accurately reflect the nodal status of internal mammary basin before the clinical application of IM-SLNB. In conclusion, the modified injection technique (periareolar intraparenchymal, high volume, and ultrasound guidance) significantly improved the IMSLN visualization rate, making the routine IM-SLNB possible in daily practice. Internal mammary sentinel lymph node biopsy could provide individual minimally invasive staging, prognosis, and decision making of the internal mammary radiotherapy for breast cancer patients, especially for clinically ALN-positive patients. REFERENCES
Internal Mammary Sentinel Lymph Node Biopsy
6. Heuts EM, van der Ent FW, von Meyenfeldt MF, et al. Internal mammary lymph drainage and sentinel node biopsy in breast cancer – a study on 1008 patients. Eur J Surg Oncol. 2009;35:252–257. 7. Shimazu K, Tamaki Y, Taguchi T, et al. Lymphoscintigraphic visualization of internal mammary nodes with subtumoral injection of radiocolloid in patients with breast cancer. Ann Surg. 2003;237:390–398. 8. Park C, Seid P, Morita E, et al. Internal mammary sentinel lymph node mapping for invasive breast cancer: implications for staging and treatment. Breast J. 2005;11:29–33. 9. Rodier JF, Velten M, Wilt M, et al. Prospective multicentric randomized study comparing periareolar and peritumoral injection of radiotracer and blue dye for the detection of sentinel lymph node in breast sparing procedures: FRANSENODE trial. J Clin Oncol. 2007;25:3664–3669. 10. Garcia-Manero M, Olartecoechea B, Royo P. Different injection sites of radionuclide for sentinel lymph node detection in breast cancer: single institution experience. Eur J Obstet Gynecol Reprod Biol. 2010;153:185–187. 11. Caudle AS, Yi M, Hoffman KE, et al. Impact of identification of internal mammary sentinel lymph node metastasis in breast cancer patients. Ann Surg Oncol. 2014;21:60–65. 12. Jones SR1, Carley S, Harrison M. An introduction to power and sample size estimation. Emerg Med J. 2003;20:453–458. 13. National Comprehensive Cancer Network. NCCN Breast Cancer Clinical Practice Guidelines in Oncology. (V. 1.2015). http:// www.nccn.org/professionals/physician_gls/PDF/breast.pdf 14. Wang L, Yu JM, Wang YS, et al. Preoperative lymphoscintigraphy predicts the successful identification but is not necessary in sentinel lymph nodes biopsy in breast cancer. Ann Surg Oncol. 2007;14:2215–2220. 15. Sun X, Liu JJ, Wang YS, et al. Roles of preoperative lymphoscintigraphy for sentinel lymph node biopsy in breast cancer patients. Jpn J Clin Oncol. 2010;40:722–725. 16. Chagpar A, Martin RC 3rd, Chao C, et al. Validation of subareolar and periareolar injection techniques for breast sentinel lymph node biopsy. Arch Surg. 2004;139:614–618. 17. Borgstein PJ, Meijer S, Pijpers RJ, et al. Functional lymphatic anatomy for sentinel node biopsy in breast cancer: echoes from the past and the periareolar blue method. Ann Surg. 2000;232:81–89. 18. Tanis PJ, Nieweg OE, Valde´s Olmos RA, et al. Anatomy and physiology of lymphatic drainage of the breast from the perspective of sentinel node biopsy. J Am Coll Surg. 2001;192:399–409. 19. Qiu PF, Liu JJ, Liu YB, et al. A modified technology could significantly improve the visualization rate of the internal mammary sentinel lymph nodes in breast cancer patients. Breast Cancer Res Treat. 2012;136:319–321.
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23. Gnerlich JL, Barreto-Andrade JC, Czechura T, et al. Accurate staging with internal mammary chain sentinel node biopsy for breast cancer. Ann Surg Oncol. 2014;21:368–374. 24. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group). Effect of radiotherapy after mastectomy and axillary surgery on
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10-year recurrence and 20-year breast cancer mortality: metaanalysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127–2135. 25. Poortmans P, Struikmans H, Kirkove C. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 years results of the EORTC Radiation Oncology and Breast Cancer Groups phase III trial 22292/10925 (meeting abstracts). Eur J Cancer. 2013;49:BA2.
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26. Cong BB, Qiu PF, Wang YS. Internal mammary sentinel lymph node biopsy: minimally invasive staging and tailored internal mammary radiotherapy. Ann Surg Oncol. 2014;21:2119– 2121. 27. Madsen EV, Aalders KC, van der Heiden-van der Loo M, et al. Prognostic significance of tumor-positive internal mammary sentinel lymph nodes in breast cancer: a multicenter cohort study. Ann Surg Oncol. 2015. [Epub ahead of print].
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